Development of 18F PET radiotracers for M2 microglia as diagnostics for multiplesclerosis pathogenesis

开发用于 M2 小胶质细胞的 18F PET 放射性示踪剂作为多发性硬化症发病机制的诊断

• 批准号: 10440539
• 负责人: Paul Anthony Stupple
• 金额: $ 28.82万
• 依托单位: MONASH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440539
• 关键词: ABCG2 gene; Adult; Affect; Affinity; Animal Model; Anti-Inflammatory Agents; Autoradiography; Binding; Binding Sites; Biological Markers; Biological Process; Brain; C57BL/6 Mouse; Caucasians; Cells; Clinical; Clinical Research; Clinical Trials; Cuprizone; Development; Diagnostic; Diagnostic Reagent; Digit structure; Disease; Disease Outcome; Dose; Equipment; Exhibits; FLT3 gene; Failure; Fluorides; Fluorine; Freezing; Future; Genes; Image; Immune; Immunohistochemistry; In Vitro; Inflammatory; Inflammatory Response; Injury; Kinetics; Laboratories; Lead; Lesion; Ligands; Link; MERTK gene; Measures; Mediator of activation protein; Medical Care Costs; Microglia; Modeling; Monitor; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Nature; Nerve Degeneration; Nervous system structure; Outcome; Pathogenesis; Pathogenicity; Patients; Penetration; Pharmaceutical Preparations; Phase; Phenotype; Positron-Emission Tomography; Predisposition; Property; Proteins; Radioactive; Radiochemistry; Receptor Protein-Tyrosine Kinases; Rodent; Route; Scanning; Signal Transduction; Slice; Solubility; Stratification; Structure; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Tracer; Translational Research; Variant; Work; blood-brain barrier permeabilization; cytokine; design; diagnostic tool; differential expression; disability; economic cost; imaging approach; improved; in vivo; kinase inhibitor; macrophage; mouse model; multiple sclerosis patient; nanomolar; nervous system disorder; next generation; non-invasive imaging; novel; patient stratification; radiochemical; radioligand; radiotracer; repaired; response; response to injury; selective expression; success; tool; treatment response; treatment strategy; uptake; young adult

Project summary Multiple sclerosis (MS) is the most common disabling neurodegenerative condition that affects young adults around the world. Despite enormous efforts for treatment discovery, progressive disability, accompanied by very significant adverse personal, medical and economic costs, remains very common. An important reason that contributes to the unenviable track record of clinical trial failure for progressive MS is our inability to monitor in a precise manner the status of MS at any given time. Although it has been established that the inflammatory cells within the brain, known as microglia, are active in the progressive phase of the disease and most likely dictate outcome, we remain unable to differentiate between MS-mediator and reparative microglia. Therefore, there is a dire need to develop techniques that identify the subsets of microglia in order to stratify patients and offer them adequate treatment. Positron emission tomography (PET) has recently gained huge success as a non-invasive imaging approach to accurately quantify biological processes within the brain. Thus far, PET imaging in MS patients has been restricted to imaging a radioactive molecule, i.e. radioligand, that binds to a protein known as TSPO. However, the recently observed variation of the TSPO gene, with some patients lacking binding of the radioligands, and its inability to distinguish the activity of microglia limits its utility as a clinical and research tool. Building on our previous results showing the selective upregulated expression of a protein by reparative microglia, we will develop radioligands that bind to this protein and can be used for diagnostic purposes via PET. This highly translational research plan will enable clinicians to classify MS in novel ways to guide therapeutic intervention in MS patients in ways not previously possible. The specific aims of this project are to (i) design and synthesize next-generation radioligands with optimized binding and CNS penetration; (ii) generate radioactive versions of leading compounds; (iii) validate the radioligands in MS mouse brain slices and assess them by PET in MS mouse models. Outcome: This work will result in a diagnostic reagent that, using imaging equipment, will help clinicians monitor the status of progressive MS in patients being treated in a manner that has never been possible before and improve the success rates of new MS drugs being tested in clinical trials.

项目总结 多发性硬化症(MS)是影响年轻人的最常见的致残性神经退行性疾病 环游世界。尽管在治疗发现方面做出了巨大努力，但进行性残疾伴随着非常严重的 巨大的不利的个人、医疗和经济成本仍然非常普遍。一个重要的原因是 导致进展性多发性硬化症临床试验失败的不令人羡慕的记录的原因是我们无法在 以精确的方式显示MS在任何给定时间的状态。尽管已经证实炎性细胞 在大脑中，被称为小胶质细胞的细胞在疾病的进展阶段活跃，很可能决定了 结果，我们仍然不能区分MS介体和修复性小胶质细胞。因此，有 迫切需要开发识别小胶质细胞亚群的技术，以便对患者进行分层并为他们提供 适当的治疗。 正电子发射断层扫描(PET)作为一种非侵入性的成像方法，最近获得了巨大的成功 准确量化大脑内的生物过程。到目前为止，多发性硬化症患者的PET成像 仅限于对与一种称为TSPO的蛋白质结合的放射性分子，即放射性配体进行成像。然而， 最近观察到的TSPO基因变异，一些患者缺乏放射性配体的结合，以及 它无法区分小胶质细胞的活动，限制了其作为临床和研究工具的实用性。建立在我们的 先前的结果表明，修复性小胶质细胞选择性上调了蛋白质的表达，我们将 开发与这种蛋白质结合的放射性配体，并可通过PET用于诊断目的。如此之高 翻译研究计划将使临床医生能够以新的方式对多发性硬化症进行分类，以指导治疗干预 以前所未有的方式治疗多发性硬化症患者。 该项目的具体目标是(I)设计和合成具有优化的下一代放射性配体 结合和中枢神经系统渗透；(2)产生先导化合物的放射性版本；(3)验证 MS小鼠脑片中的放射性配基，并在MS小鼠模型中用PET进行评估。 结果：这项工作将产生一种诊断试剂，使用成像设备，将帮助临床医生监测 进展性多发性硬化症患者的状态正在以前所未有的方式接受治疗和 提高多发性硬化症新药临床试验成功率。